A Role in Schizophrenia
Schizophrenia research has pointed toward mitochondrial dysfunction as a mechanism that could help explain some of the disorder’s underlying biology.
Bartal et al. (2023) ran a systematic meta-analysis looking at genes responsible for building mitochondrial ribosomes — the Mitochondrial Ribosomal Proteins Large and Small (MRPL/MRPS) gene families — in people with schizophrenia. Several of these genes were downregulated compared to healthy controls, with two reaching statistical significance in both brain and blood samples: MRPL4 and MRPS7. Because these are regulatory genes, their downregulation could mean the cell isn’t producing enough of the essential building blocks needed for oxidative phosphorylation and ATP production. Notably, when the analysis was restricted to male participants only, 16 MRP genes showed significant downregulation — a much larger effect than in the combined sample.
Idotta et al. (2024) cultured neural stem/progenitor cells collected from the olfactory neuroepithelium of both schizophrenic and healthy participants — a technique that offers a way to study living neural-lineage cells without a brain biopsy. Cells from the schizophrenic participants showed significantly lower mitochondrial ATP production.
Kondo et al. (2022) analyzed RNA from postmortem brain samples of schizophrenic patients. They used pathway analysis software to identify possible effects on the proteins encoded by downregulated genes, landing on impaired oxidative phosphorylation and mitochondrial dysfunction.
Das et al. (2022) examined postmortem brain tissue tissue and found the dorsolateral prefrontal cortex had significantly higher mitochondrial DNA (mtDNA) copy numbers and significantly more mtDNA deletions in schizophrenic patients than in controls, along with lower activity in Complex I of the electron transport chain and a lower concentration of Complex I proteins — indicating impaired energy production at the cellular level.
MELAS- A Mitochondrial Dysfunction Diagnosis
A case report by Ge et al. (2017) offers a striking illustration of mitochondrial dysfunction in the brain. The patient experienced sudden-onset inability to understand written words, trouble with normal movement, and seizures, on top of hearing loss that had developed gradually over the previous three years. A CT scan revealed brain lesions, and genetic testing found a mitochondrial DNA mutation (A3243G) consistent with MELAS (Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like episodes). She was treated with L-arginine, phenobarbital, coenzyme Q, and levothyroxine, and improved; six months later, she was seizure-free.
One detail from the case discussion stood out: mitochondrial mutations don’t necessarily affect the whole body. Inherited mutations do, since they’re present from the earliest cell divisions. But a mutation that arises during a person’s lifetime — from radiation exposure, for example — only affects the cells descended from that one mutated cell, and won’t be passed to offspring unless it happens to occur in a germ cell.
The authors suggest that inadequate ATP production due to mitochondrial dysfunction could impact plasma membrane potential. Without enough ATP, Na+/K+-ATPase and Ca2 +-ATPase won’t be able to maintain proper Na+ and Ca2 + concentrations across the cell membrane. When intracellular calcium rises, demyelination, dysregulation of apoptosis, and issues with storage, release or uptake of neurotransmitters can follow.
The Takeaway
Mitochondrial energy production is foundational to the functioning of our physiology, and psychiatric and neurological symptoms can be among the effects seen when it is impaired.
The content of this blog is for educational purposes and is not intended as medical advice. Please work with a qualified healthcare provider for personalized guidance.
References
Bartal, G., Yitzhaky, A., Segev, A., & Hertzberg, L. (2023). Multiple genes encoding mitochondrial ribosomes are downregulated in brain and blood samples of individuals with schizophrenia. The World Journal of Biological Psychiatry, 24(9), 829–837.
Das, S. C., Hjelm, B. E., Rollins, B. L., Sequeira, A., Morgan, L., Omidsalar, A. A., Schatzberg, A. F., Barchas, J. D., Lee, F. S., Myers, R. M., Watson, S. J., Akil, H., Bunney, W. E., & Vawter, M. P. (2022). Mitochondria DNA copy number, mitochondria DNA total somatic deletions, Complex I activity, synapse number, and synaptic mitochondria number are altered in schizophrenia and bipolar disorder. Translational Psychiatry, 12(1).
Ge, Y.-X., Shang, B., Chen, W.-Z., Lu, Y., & Wang, J. (2017). Adult-onset of mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) syndrome with hypothyroidism and psychiatric disorders. ENeurologicalSci, 6, 16–20.
Idotta, C., Pagano, M. A., Tibaldi, E., Cadamuro, M., Saetti, R., Silvestrini, M., Pigato, G., Leanza, L., Peruzzo, R., Meneghetti, L., Piazza, S., Meneguzzo, P., Favaro, A., Grassi, L., Toffanin, T., & Brunati, A. M. (2024). Neural stem/progenitor cells from olfactory neuroepithelium collected by nasal brushing as a cell model reflecting molecular and cellular dysfunctions in schizophrenia. The World Journal of Biological Psychiatry, 25(6), 317–329.
Kondo, M. A., Norris, A. L., Yang, K., Cheshire, M., Newkirk, I., Chen, X., Ishizuka, K., Jaffe, A. E., Sawa, A., & Pevsner, J. (2022). Dysfunction of mitochondria and GABAergic interneurons in the anterior cingulate cortex of individuals with schizophrenia. Neuroscience Research, 185, 67–72.
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